U.S. Pat. No. 3,652,589 discloses a class of analgesic cycloalkanol-substituted phenol esters having a basic amine group in the cycloalkyl ring. The compound (1RS, 2RS) trans-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)cyclohexanol, commonly known as tramadol, is specifically disclosed therein. A series of articles pertaining to the pharmacology, toxicology and clinical studies of tramadol are found in Arzneim, Forsch (Drug Res.), 28(l), 114 (1978). Driessen et al., Arch. Pharmacol., 341, R104 (1990) disclose that tramadol produces its analgesic effect through a mechanism that is neither fully opioid-like nor non-opioid-like. The Abstracts of the VI th World Congress on Pain, Apr. 1-6 (1990) discloses that tramadol hydrochloride is an orally active pure agonist opioid analgesic. However, clinical experience indicates that tramadol lacks many of the typical-side effects of opioid agonists, e.g., respiratory depression (W. Vogel et al., Arzneim, Forsch, (Drug Res.), 28(l), 183 (1978)), constipation (I. Arend et al., Arzneim, Forsch, (Drug Res.), 28(l), 199 (1978)), tolerance (L. Flohe et al., Arzneim, Forsch, (Drug Res.), 28(l), 213 (1978)), and abuse liability (T. Yanagita, Arzneim, Forsch. (Drug Res.), 28(l), 158 (1978)). When given at a dose of 50 mg by rapid i.v. injection, tramadol may however, produce certain side effects unique to tramadol including hot flushes and sweating. Despite theses side effects, tramadol's combination of non-opioid and opioid activity makes tramadol a very unique drug. Tramadol is currently being marketed by Grunenthal GMBH in Germany as an analgesic.
Opioids have for many years been used as analgesics to treat severe pain. However, they produce undesirable side effects which place limitations on their use. The side effect problems are well documented in the literature. See, Jaffe, J. in "Goodman and Gilman's The Pharmacological Basis of Therapeutics", 8th edition; Gilman et al.; Peragamon Press, New York, 1990; Chapter 22, pages 522-573, wherein it is disclosed that morphine and its congeners, e.g., codeine, hydrocodone and oxycodone, are opioid agonist analgesics that exhibit side effects such as respiratory depression, constipation, tolerance and abuse liability.
To reduce the side effect problems, opioids have been combined with other non-opioid analgesic agents so as to reduce the amount of opioid needed to produce equivalent analgesia. The reduced amount of opioid generally reduces the number and degree of the side effects. It has been claimed that some of these combination products also have the advantage of producing a synergistic analgesia effect. For example, A. Takemori Annals New York Acad. Sci., 281, 262 (1976) discloses that compositions including combinations of opioid analgesics with drugs other than analgesics exhibit a variety of effects, i.e., subadditive (antagonistic), additive or superadditive. R. Taber et al., J. Pharm. Expt. Thera., 169(1), 29 (1969) disclose that the combination of morphine and methadone, another opioid analgesic, exhibited only an additive effect. U.S. Pat. No. 4,571,400 discloses that the combination of dihydrocodeine, another opioid analgesic, and ibuprofen, a non-opioid analgesic, provides superadditive effects when the components are within certain ratios. A. Pircio et al., Arch. Int. Pharmacodyn., 235, 116 (1978) report superadditive analgesia with a 1:125 mixture of butorphanol, another opioid analgesic, and acetaminophen (APAP), a non-opioid analgesic, whereas a 1:10 mixture did not show any statistically-significant superadditive analgesia.
However, the prior art, does not suggest or disclose that tramadol, an "atypical" opioid analgesic, can or should be combined with another analgesic, particularly an opioid analgesic, to lessen the side effects of each; or to yield a composition that exhibits superadditive analgesia.